The objective of this project is to determine the molecular and neurophysiological mechanisms in the CNS that cause time-dependent changes in the hypoxic ventilatory response (HVR) with chronic hypoxemia. We propose using amino acid neurotransmission in the CNS. Further, we hypothesize that the molecular events leading to these changes represent specific responses to increased Po2 and secondary responses to changes in neural activity. Chronic hypoxia, carotid body denervation and chronic administration of receptor agonists and antagonists to specific sites in the CNS will be used to determine the independent effects of Po2 versus neural activity. Microinjection or reverse microdialysis of receptor agonists and antagonists will be used to quantify the role of glutamate, GABA and nitric oxide in CNS nuclei along the HVR reflex pathway. Neurotransmitter levels, amino acid receptor proteins and their mRNA will be measured with microdialysis/HPLC, autoradiography and quantitative RT-PCR. We will use similar methods to test the hypotheses that different mechanisms are involved in ventilatory acclimatization at different times during intermittent and chronic hypoxia, even through the measured change in HVR may be identical. The specific suite of mechanisms operative at any time during hypoxic exposure is predicted to depend on the order and nature and nature of the specific mechanisms that have been elicited previously, The role of neuromodulation by dopamine in explaining differences in the HVR with intermittent and continuous hypoxia will be studied in humans. Finally, we will study changes in the neural control of O2 demand (i.e. resting Vo2) during chronic hypoxia in rats. We hypothesize that the same changes in amino acid neurotransmission studied above will occur in CO2-sensitive neurons in medulla also, and these explain changes in neural control of Vo2 during chronic hypoxia. The results should generate new hypotheses about ventilatory control during chronic hypoxemia, and suggest new treatments for chronic lung disease.